Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis

By Z. Fan, A. Wirth, D. Chen, C. Wruck, M. Rauh, M. Buchfelder, N. Savaskan. Oncogenesis, 2017

622 citations recorded by the source corpus.

Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc−) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles’ heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/e9d38e30c451bc48a29bdfac7ad5a10f250b8b0d

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Citations in the corpus

Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “166 These ﬁ ndings indicate that the ferroptosis-promoting role of KEAP1 potentially at least partly accounts for its tumor-suppressive function.”
The Development of the Concept of Ferroptosis (2018, neutral): “[152,153] can protect cells from ferroptotic death by upregulating system Xc [132,154], and was found to be commonly overactivated in various cancers [155,156].”
NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis (2019, background): “Accordingly, the level of NRF2 has been directly correlated with ferroptosis sensitivity, as increased expression of NRF2 prevents ferroptosis, whereas decreased NRF2 enhances the sensitivity of cancer cells to pro-ferroptotic agents [57,59].”
Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. (2019, neutral): “In addition to p53, the electrophile responsive transcription factor Nrf-2 can also suppress ferroptosis in tumor cells (Fan et al., 2017) or in neuronal cultures when activated selectively in glial cells (Haskew-Layton et al.”